Particulate matter increases connexin 43 expression and exacerbates endothelial barrier disruption.

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OBJECTIVES: Particulate Matter (PM) air pollution is known to exacerbate cardiopulmonary diseases. We previously demonstrated that PM mediates endothelial injury and barrier disruption by modulating the endothelial cytoskeleton and cell-cell junctions, but the effects of PM exposure on cell-cell communication and gap junction activity are still unknown. METHODS: This study focused on the characterization of PM-regulated endothelial dysfunction through connexin 43 (Cx43), the most abundant gap junction protein expressed in lung endothelial cells (ECs), using cultured human lung endothelial cells and a well-characterized PM sample. RESULTS: PM exposure induced a time-dependent increase of Cx43 in human lung ECs at both the mRNA and protein levels. N-acetylcysteine (NAC), a reactive oxygen species (ROS) scavenger, significantly suppressed PM-induced Cx43 expression. Cx43 proteins on the plasma membrane and ER/Golgi apparatus were elevated in response to a PM challenge. In addition, PM induced gap junction activity, which was indicated by green fluorescence dye transfer between two adjacent ECs. Moreover, GAP27, a selective Cx43 channel inhibitor, attenuated PM-induced human lung EC barrier disruption, which was reflected by rescued trans-endothelial electrical resistance (TER) with an electric cell-substrate impedance sensing system. Moreover, knocking down Cx43 alleviated PM-induced myosin light chain (MLC) phosphorylation. CONCLUSIONS: These results strongly suggest that Cx43 plays a key role in PM-mediated endothelial barrier disruption and signal transduction. Cx43 may be a therapeutic target in PM-mediated cardiopulmonary disorders.

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